ESRD in Lupus: A Work in Progress?

Declines in disease risk seen since the 1970s, but recent stats have leveled off

Action Points

The risk of end-stage renal disease declined among patients with lupus nephritis during the past several decades, although this appears to have plateaued recently.

Note that the reason for the lack of further risk reduction in ESRD in the 1990s and 2000s is not known, but is speculated to be the result of the way currently available and effective treatments are deployed.

The risk of end-stage renal disease (ESRD) declined among patients with lupus nephritis during the past several decades, although this appears to have plateaued recently, a meta-analysis found.

In the 1970s, the 5-year estimated risk of ESRD for patients with lupus nephritis was 16% (95% CI 14-17), falling to 11% (95% CI 10-12) in the mid-1990s, according to Michael M. Ward, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, in Bethesda, Md.

In addition, the 10- and 15-year risks also decreased during the 1970s and 1980s, leveling off in the mid-1990s at 17% (95% CI 16-18) and 22% (95% CI 20-23), respectively, the researchers reported online in Arthritis & Rheumatology.

Then, in the late 2000s, there was an apparent increase in risk, a pattern that "suggests limitations in the effectiveness of, or access to, current treatments," Ward and colleagues observed.

Risks and Treatments

More than half of patients with systemic lupus erythematosus develop nephritis, and this common complication increases mortality risk more than 25-fold. Previous estimates have suggested that ESRD may develop in 10% to 30% of patients with nephritis, but those estimates included only selected groups, and major changes have occurred over time in treatment.

"Although there is a clinical impression that ESRD risks in lupus nephritis have decreased over the past 40 years, few studies have examined changes in this risk," the researchers wrote.

Some of the change in ESRD risk are likely to reflect the marked changes have occurred in the treatment of lupus nephritis during those decades. In 1966, more than half of patients were treated with glucocorticoids alone, a number that declined to 9% by 2010. During the 1980s, combinations of steroids and azathioprine or cyclophosphamide were favored, and high-dose cyclophosphamide became standard for severe disease.

Then in the 1990s, mycophenolate mofetil (CellCept) was introduced and induction and various maintenance regimens have since been evaluated and used.

"Contemporary aggregate estimates of the risk of ESRD are [therefore] needed to provide patients with accurate prognostic information," Ward and colleagues stated.

Trends and Reasons

Accordingly, they performed a systematic review of the literature published from 1971 to 2015, identifying 187 studies that included more than 18,000 patients who were followed for a median of 5 years.

In developing countries, the 5- and 10-year risks were stable during the 1980s and 1990s at 12% (95% CI 11-13) and 19% (95% CI 18-20), respectively, with a slight decline in the 15-year risk after 2000.

The 5-year risks were similar in developed and developing countries after 2000, although the 15-year risks in developing countries were 10 percentage points higher.

In studies that reported ESRD risks according to histologic class in the developed world, the analysis determined that the risks were highest for class IV nephritis, with risks of 19% (95% CI 12-29) at 5 years, 33% (95% CI 22-44) at 10 years, and 44% (95% CI 32-56) at 15 years.

"The most prevalent recent change in this subset of patients has been a shift in treatment away from high-dose cyclophosphamide, raising the question of whether these new treatment approaches result in different long-term outcomes," Ward and colleagues wrote.

As to why the decrease in risk appeared to level off in the 1990s, "it is possible that the plateau reflects lack of progress in the way currently available and effective treatments are deployed," they suggested. "This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence."

The reasons for the increase observed during the late 2000s is unclear, and "did not appear to be attributable to increased representation of ethnic minorities, who may be more likely to develop ESRD, in recent studies," they noted.

And with regard to the observed recent uptick in risk, "the underlying heterogeneity of the studies necessitates that we exercise caution in drawing conclusions from these observations, such as whether there has been a trend towards an increase in risk since the later 2000s," said Howard R. Smith, MD, who directs the lupus clinic at the Cleveland Clinic.

Smith, who was not involved in the study, also noted that his experience has been somewhat different in recent years than what was reported in the meta-analysis.

"My impression is that, overall, my patients with lupus nephritis have done considerably better since the 1980s, and even better since 2000. In the past decade, we have been more vigilant in treating comorbid conditions such as hypertension, cardiovascular disease, and hyperlipidemia," he told MedPage Today.

"These entities have an impact on renal outcomes, and I assume that attention to those comorbid conditions has translated to better outcomes," he said.

"A number of studies to date highlight extremely poor medication adherence among [lupus] patients and find that risk factors for nonadherence, including younger age, lower socioeconomic status and black race, are similar to the predictors of poorer overall outcomes," Feldman and Costenbader wrote.

A second major obstacle to improved outcomes is access to subspecialty care, according to Feldman and Costenbader. Many patients live in areas with no local access to rheumatologists or nephrologists, and "copayment costs, appointment delays based on insurance status, and language barriers may delay time to diagnosis and treatment, particularly among lower socioeconomic status individuals."

"We certainly have room to improve the way patients access early and high quality healthcare, obtain and adhere to medications, and participate in the medication decision-making process," the editorialists stated.

"The treatment of lupus nephritis is still very challenging," Smith said. "Outcomes have improved, but there is still much work to be done. Newer modalities and therapies directed at novel mechanisms may lead to better outcomes, but investigators must conduct precise studies that ask directed questions," he concluded.

Ward and co-authors disclosed no relevant relationships with industry.

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